Guideline consensus: Evidence-based medicine guidelines for the treatment of motor symptoms in middle and late stages of Parkinson's disease in China

Parkinson's disease (PD) is a common degenerative disease of the central nervous system.
As the disease progresses to the middle and advanced stages, the emergence of PD complications makes it very difficult to treat
.
In recent years, there has been more new evidence-based medical evidence for the treatment and management of advanced PD in the world

01 Treatment of sports complications

Movement complications are common symptoms of mid-to-late PD, including symptom fluctuations, dyskinesias, etc.
, and their onset is related to disease progression and impulse stimulation caused by oral levodopa
.
There is still a lack of drugs with evidence-based medical evidence that delay or improve the progression of PD.

1 fluctuating symptoms

Mainly include: (1) curative effect decline or deterioration at the end of the dose; (2) on-off phenomenon; (3) unpredictable "off" period; (4) no "on" period; (5) "on" period delayed
.

Recommendations:

For patients with end-of-dose deterioration, first try to adjust the diet and the way of administration, including diet redistribution and restriction of protein intake (C-level recommendation), eradication of Helicobacter pylori therapy (B-level recommendation), reduce the dose of each medication and Increase the frequency of medication
.

If the method and time of adjusting the medication are not enough to effectively improve the terminal deterioration, consider replacing the long-acting levodopa preparations, including levodopa/carbidopa controlled-release tablets (grade B recommendation) and levodopa/carbidopa Pa sustained-release capsules (A grade recommendation)
.

If the above adjustments are invalid, or long-acting formulations of levodopa cannot be obtained, additional drugs can be added, including DAs (pramipexole sustained-release tablets and immediate-release tablets, ropinirole ordinary and sustained-release tablets, rotivastin Transdermal patches, injection of apomorphine and apomorphine sublingual lozenges are all A-level recommendations), MAO-B inhibitors (rasagiline A-level recommendation, selegiline B-level recommendation, safinamide and Zonisamide is recommended for grade A), COMT inhibitors (entacapone, opikapone recommended for grade A, tocapone is not recommended), adenosine A2A antagonist (recommended for itraphylline A grade) And amantadine (grade D recommendation)
.

It should be noted that some of the above drugs may increase the risk of dyskinesia
.
In addition, attention should be paid to the adverse reactions related to DAs, and elderly patients should be used with caution; for the treatment of "on-off" phenomenon, long-acting DAs, subcutaneous injection of apomorphine and levodopa gel should be considered; for unpredictable "off" In addition to the above strategies, an on-demand remedial strategy can be considered, including subcutaneous injection of apomorphine, sublingual apomorphine, and inhalation of levodopa preparations.

2 Dyskinesia

Dyskinesia often manifests as involuntary dance-like and dystonia-like movements, which can involve the head, face, limbs, and trunk
.
According to the relationship between the onset of dyskinesia and the administration of levodopa, it can be divided into dose peak dyskinesia, bipolar dyskinesia, and "off" dystonia

Recommendations:

When improving the patient's "off" period, pay attention not to increase the troublesome dyskinesia
.
For mild dyskinesia, if it does not affect the patient's daily life, no active treatment is required

You can first try to reduce the dose of dopaminergic drugs.
If the patient cannot tolerate the poor control of motor symptoms caused by the dose reduction, you can appropriately increase the frequency of levodopa taking, add amantadine therapy (A grade recommendation) or add general Laxor (grade B recommendation); if the curative effect is poor or cannot tolerate the adverse reactions of amantadine, you can consider adding clozapine (grade A recommendation), but you need to pay attention to the adverse reactions such as agranulocytosis
.

In addition to the above strategies, consider using levodopa/carbidopa intestinal gel for on-demand replenishment (level A recommendation)
.
The efficacy of levetiracetam in the treatment of dyskinesia is uncertain (level D recommendation)

02 Treatment of levodopa resistance symptoms

As the PD disease progresses, the lesions begin to involve structures other than the dopaminergic system, including the brain stem and cerebral cortex.
Therefore, patients may experience motor symptoms that are not effective for levodopa treatment in the advanced stage, called levodopa treatment resistance symptoms
.

1 Gait and balance disorders

Due to the involvement of non-dopaminergic pathways, the treatment of gait and balance dysfunction is very challenging.
Even if dopaminergic drugs have been adjusted to the best, there are still a considerable number of patients who cannot improve their symptoms
.
The currently available strategies include drug therapy, rehabilitation, and surgical treatment that act on transmitter pathways other than dopaminergic

(1) Frozen gait (FOG)

Recommendations:

The treatment of FOG should first evaluate the time when the patient appears FOG under the current treatment, and determine the specific type of FOG of the patient
.

For dopaminergic FOG, you should first try to increase the dose of levodopa (levodopa and levodopa/carbidopa gel are B-level recommendations).
If you cannot tolerate or are not satisfied with the effect, you can consider adding other dopamines.
Energy drugs, such as DAs (Rotigotine scalp patch and pramipexole are all recommended at level C), MAO-B inhibitors, etc.
(Rasagiline is recommended at level B and selegiline is recommended at level C)
.

If the patient appears mainly in the "off" period, FOG can be relieved by strategies to minimize the fluctuation of symptoms (such as shortening the dosing interval, etc.
); if the patient develops FOG at night, a sustained-release dosage form can be given before going to bed to reduce nighttime The "off" period achieves the purpose of alleviating FOG
.

Non-dopaminergic drugs may improve dopamine-resistant FOG, such as cholinesterase inhibitors (Galantamine C-level recommendation, Rivavastigmine B-level recommendation), antidepressants (SSRIs and SNRIs are both C-level recommendation) , Methylphenidate (grade B recommended), combination of droxidopa and entacapone (dopamine-resistant FOG) (grade C recommended), ittraphylline (grade C recommended) and amantadine (grade D recommended) )
.

However, it should be noted that dopamine-resistant FOG is not completely ineffective against dopaminergic drugs.
The treatment of such FOG should be treated with other non-dopaminergic drugs under the best dopaminergic treatment
.
The treatment of dopamine-induced FOG should reduce the use of dopaminergic drugs.

(2) Other treatments for gait and balance disorders

Recommendations:

Other gait and balance disorders may be caused by external involvement of the dopaminergic system.
Therefore, when high-dose dopaminergic drugs cannot be improved, other drugs, such as cholinesterase inhibitors (donepezil, riva, Stigmine is recommended at level B), adrenergic drugs (after STN-DBS, recommended at level B for methylphenidate), and istraphylline (recommended at level C)
.
However, drug therapy is often not effective for gait and balance disorders.
Some physical rehabilitation treatments (grade B recommendation) may also be effective means to improve gait and balance disorders
.
If the above-mentioned optimal treatment still fails to achieve satisfactory results, surgery can be considered after full evaluation (bilateral STN-DBS and GPI-DBS are recommended for grade B, and PPN-DBS for grade C)
.
At the same time, consider the combined use of in vitro regulation technology and physical therapy for treatment
.

2 abnormal posture

Humpback, trunk flexion disease, Pisa syndrome, cervical flexion such as: severe axial abnormal posture, including advanced PD patients may experience
.
For postural abnormalities that do not respond well to levodopa, physical therapy (level B recommendation, level 2 evidence) and orthosis adjuvant therapy can be considered to improve symptoms.
Downhill walking training can maintain normal thoracic posture in PD patients
.
Intramuscular injection of botulinum toxin or lidocaine, STN-DBS may be effective for some patients with trunk flexion, but the current studies are case reports and small sample open trials, and the evidence is limited
.

3 Speech and swallowing disorders

With the aggravation of symptoms, speech and swallowing disorders become more obvious in patients with advanced PD.
There is no effective treatment at present.
Rehabilitation treatments for speech and swallowing functions can be used to improve symptoms, such as Li-Shefman speech therapy (B Level recommendation, Level 3 evidence), reading aloud and singing may be effective
.
In addition, swallowing function training and video-assisted swallowing function training can improve the swallowing function of PD patients, and studies have found that video-assisted swallowing function training is more effective than traditional swallowing function training
.